844ins68 Polymorphism Research Articles

Methionine synthetase A2756G and Cystathionine-β-synthase 844ins68 polymorphisms and coronary artery disease: a meta-analysis

Objective: Methionine synthetase (MS) A2756G and Cystathionine-β-synthase (CBS) 844ins68 gene polymorphisms were indicated to be associated with increased coronary artery disease (CAD) risk. Nevertheless, because the results of each experiment are different, there is no consensus till now. This meta-analysis aimed to clarify the relationship between MS gene A2756G and CBS gene 844ins68 polymorphisms and CAD.Methods: 11,555 participants from 24 individual studies, 2162 participants from 6 individual studies were included in the MS gene A2756G and CBS 844ins68 gene polymorphisms meta-analysis respectively. To determine whether MS gene A2756G or CBS gene 844ins68 polymorphism was associated with CAD risk, a random or fixed-effect genetic model was adopted using pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).Results:MS gene A2756G polymorphism was significantly associated with CAD under recessive (OR: 1.400, 95% CI: 1.119-1.751, P=0.003) and homozygous genetic models (OR: 1.360, 95% CI: 1.084-1.706, P=0.008). In the African subgroup, the association was significant under the allelic, recessive, dominant, heterozygous, homozygous and additive (P<0.05) genetic models. In the Asian subgroup, the association was significant under the allelic, recessive and homozygous genetic models (P<0.05). No significant association was found between CBS 844ins68 gene polymorphism and CAD under all of the genetic models (P>0.05).Conclusions:MS gene A2756G polymorphism was significantly associated with increased CAD risk, especially in the African and Asian population. The G allele carriers of MS gene A2756G polymorphism were more susceptible to be suffered from CAD disease than others.

Homocysteine thiolactone and other sulfur-containing amino acid metabolites are associated with fibrin clot properties and the risk of ischemic stroke

Homocysteine (Hcy) and Hcy-thiolactone (HTL) affect fibrin clot properties and are linked to cardiovascular disease. Factors that influence fibrin clot properties and stroke are not fully understood. To study sulfur-containing amino acid metabolites, fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to stroke, we analyzed plasma and urine from 191 stroke patients (45.0% women, age 68 ± 12 years) and 291 healthy individuals (59.7% women, age 50 ± 17 years). Plasma and urinary levels of sulfur-containing amino acid metabolites and fibrin clot properties were significantly different in stroke patients compared to healthy individuals. Fibrin CLT correlated with fibrin Absmax in healthy males (R2 = 0.439, P = 0.000), females (R2 = 0.245, P = 0.000), female stroke patients (R2 = 0.187, P = 0.000), but not in male stroke patients (R2 = 0.008, P = ns). Fibrin CLT correlated with age in healthy females but not males while fibrin Absmax correlated with age in both sexes; these correlations were absent in stroke patients. In multiple regression analysis in stroke patients, plasma (p)CysGly, pMet, and MTHFR A1298C polymorphism were associated with fibrin Absmax, while urinary (u)HTL, uCysGly, and pCysGly were significantly associated with fibrin CLT. In healthy individuals, uHTL and uGSH were significantly associated with fibrin Absmax, while pGSH, and CBS T833C 844ins68 polymorphism were associated with fibrin CLT. In logistic regression, uHTL, uHcy, pCysGly, pGSH, MTHFR C677T polymorphism, and Absmax were independently associated with stroke. Our findings suggest that HTL and other sulfur-containing amino acid metabolites influence fibrin clot properties and the risk of stroke.

Global DNA Methylation Levels Viz-a-Viz Genetic and Biochemical Variations in One Carbon Metabolic Pathway: An Exploratory Study from North India.

Despite the importance of one carbon metabolic pathway (OCMP) in modulating the DNA methylation process, only a few population-based studies have explored their relationship among healthy individuals. This study aimed to understand the variations in global DNA methylation levels with respect to selected genetic (CBS 844ins68, MTRR A66G, MTR A2756G, and MTHFR C677T polymorphisms) and biochemical (folate, vitamin B12, and homocysteine) markers associated with OCMP among healthy North Indian adults. The study has been conducted among 1095 individuals of either sex (69.5% females), aged 30-75 years. A sample of 5 mL of blood was collected from each participant. Homocysteine, folate, and vitamin B12 levels were determined using the chemiluminescence technique. Restriction digestion was performed for genotyping MTRR A66G, MTR A2756G, and MTHFR C677T polymorphisms and allele-specific PCR amplification for CBS 844ins68 polymorphism. Global DNA methylation levels were analyzed using ELISA-based colorimetric technique. Of the selected genetic and biochemical markers, the mutant MTRR A66G allele was positively associated with global DNA methylation levels. Further, advanced age was inversely associated with methylation levels. MTRR 66GG genotype group was hypermethylated than other genotypes in folate replete and vitamin B12 deficient group (a condition prevalent among vegetarians), suggesting that the G allele may be more efficient than the wild-type allele in such conditions. Global DNA methylation levels appeared to be more influenced by genetic than biochemical factors. MTRR 66G allele may have a selective advantage in vitamin B12 deficient conditions. Further research should be undertaken to understand how genetics affects epigenetic processes.

Cognitive impairment viz-a-viz genetic and biochemical variations in one carbon metabolic pathway: A population-based study from North India

Disturbances in the one‑carbon metabolic pathway (OCMP) have been reported to be associated with cognitive impairment (CI). The study aimed to examine the association of MTR A2756G, MTRR A66G, and CBS 844ins68 polymorphisms present at critical steps of OCMP with CI independently and in light of vitamin B12, folate deficiencies, and hyperhomocysteinemia. The study also aimed to understand gene-gene interactions among selected markers linked with OCMP in CI using multifactor dimensionality reduction (MDR) analysis. A total of 808 individuals, aged 30–70 years of either sex, were recruited from Haryana, North India. Participants were screened for CI using MMSE. Individuals with mild CI were considered as case-1 and moderate/severe CI as case-2. Sociodemographic data were collected using an interview schedule. Biochemical and genetic analyses were performed using standard protocols. In the present study, CI was not found to be associated with MTR A2756G or CBS 844ins68 polymorphisms. AG and AA+AG genotypes of MTRR A66G polymorphism, with GG as the reference genotype, were found to pose 1.97 to 2.59-folds significantly increased risk for case-1 and case-2 CI. These associations, however, lost statistical significance for normal levels of vitamin B12 and homocysteine. In MDR analysis, two-loci models with MTHFR+MTRR for case-1 and MTR+MTRR for case-2 were found to have the highest TA% and CVC. Overall, MTRR A66G polymorphism appears to be a risk factor for CI in the studied population. Vitamin B12 seems to modulate the association of CI with MTRR A66G. MDR analysis suggests the involvement methionine cycle of OCMP in CI.

Association of CBS 844ins68, MTR A2756G and MTRR A66G gene polymorphisms with depression: A population-based study from North India

BackgroundDepression is one of the major global health problem currently affecting about 350 million people worldwide. Its cause is a multi-factorial which involves a complex mechanism of social, physiological, and biological factors. Mutations of genes in one-carbon metabolic pathway such as cystathionine-β-synthase (CBS 844ins68), methyltransferase (MTR A2756G) and methyltransferase reductase (MTRR A66G) have been implicated in various neurological disorders. ObjectiveIn the present study, we attempted to understand the association of these gene polymorphisms with depression among a North Indian population. MethodsA total of 808 participants aged between 30‐ and 70 years of either sex were recruited through door-to-door household survey. Depression status was identified by administering BDI-II. Genotyping of the selected gene polymorphisms were performed following previously reported protocols. ResultsThe result revealed that only MTR A2756G gene polymorphism was significantly associated with mild depression [OR 1.65 (95 % CI: 0.05–2.62) p = 0.03] but not with moderate and severe depression among the studied population. Since CBS, MTR and MTRR genes are found in OCMP, MTR A2756G gene polymorphism was found to be associated with mild depression but not with CBS 844in68 and MTRR A66G gene polymorphisms in the present study. ConclusionIdentification of susceptible genes involved in depressive disorder and early screening for mild depression may create better opportunity for timely intervention and further improve the quality of life.

Relationship of MTHFD1 G1958A and CBS 844ins68 polymorphism with congenital heart defects in North Indian population (Jammu and Kashmir): A case-control study

Objectives: There are many multifactorial causes for Congenital Heart Defects (CHDs) in which both genetic and non-genetic factors play role. MTHFD1 and CBS are two of the key enzymes that plays pivotal role in the metabolic pathway of homocysteine. Most of the studies revealed that genes involved in folate/homocysteine pathways are involved in the occurrence of CHDs. The present study was planned to investigate the role of common polymorphisms in MTHFD1 and CBS gene in children with CHD in Jammu region of Jammu and Kashmir UT. Material and Methods: A total of 160 (80 CHD patients and 80 controls) children were enrolled for the present case-control study. After extraction of genomic DNA genotyping of SNP MTHFD1 G1958A(rs2236225) was done by PCR-RFLP and CBS 844ins68 polymorphism was done by PCR technique. Results: Our results show that there is no significant association between MTHFD1G1958A and CBS 844ins68 polymorphism with CHD. In case of SNP MTHFD1 G1958A allele A found to be higher in both patient and control group and inCBS 844ins68 polymorphism frequency of risk allele ‘I’ found higher in cases (0.06) as compared to controls (0.04). The homozygous genotype for 844ins68 (II) was found absent in both the patients and control group. Conclusion: We conclude that both MTHFD1 G1958A and CBS 844ins68 polymorphism were not found to be genetic risk factor in the development of CHD in population of Jammu region of Jammu and Kashmir UT.

Association between cystathionine beta-synthase c.844ins68 polymorphism and risk of non-syndromic cleft lip/palate: A meta-analysis of family-based and case-control studies

Both genetics and environmental factors play a role in the occurrence of non-syndromic cleft lip/palate (NSCL/P). This meta-analysis evaluated the association between cystathionine beta-synthase (CBS) c.844ins68 polymorphism and risk of NSCL/P in family-based and case-control studies. The PubMed, Web of Science, Scopus, and Cochrane Library databases were searched for articles published until September 2018. RevMan 5.3 software was used to calculate the odds ratio (OR) for the association between CBS c.844ins68 polymorphism and risk of NSCL/P by using five genetic models in the studies. The transmission disequilibrium test (TDT) was conducted for family-based studies. Three case-control and three family-based studies were evaluated. Based on the analysis of five genetic models, risk of NSCL/P was not related to CBS c.844ins68 polymorphism in case-control studies. The results of family-based studies did not show any association between the CBS c.844ins68 allele and NSCL/P either. The results of this meta-analysis showed that there was no association between CBS c.844ins68 polymorphism and risk of NSCL/P; therefore, this polymorphism does not play a role in susceptibility to NSCL/P.

CBS 844ins68, MTR A2756G and MTHFR C677T gene polymorphisms in hyperhomocysteinemia: A study among a non-tribal population group with East Asian ancestry (India)

Hyperhomocysteinemia (Hhcy) is reported to be one of the non-traditional risk factors for cardiovascular diseases. Mutation of genes in one-carbon metabolic pathway (homocysteine metabolism pathway) like methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and cystathionine beta synthase (CBS) have been implicated in hyperhomocysteinemia. The present study is an attempt to understand the association of CBS 844ins68, MTR A2756G and MTHFR C677T gene polymorphisms with hyperhomocysteinemia among a non-tribal population of Manipur, India. A total of 200 individuals from both sexes age ranging between 35 yrs. to 65 yrs. were randomly recruited for the present study. Genotyping of MTHFR C677T, MTR A2756G and CBS 844ins68 gene polymorphisms and analysis of homocysteine levels were done using standard protocols. Of the recruited individuals, 70% were classified as hyperhomocysteinemia cases and 30% were classified as normal homocysteine controls. Results indicate that none of the selected gene polymorphisms were found to be associated with hyperhomocysteinemia in the presently studied population group. However, individuals with TT genotype of MTHFR C677T gene polymorphism are bound to have hyperhomocysteinemia. Further, this TT genotype mediated hyperhomocysteinemia could be lethal among the individuals who have NI genotype of CBS 844ins68 gene polymorphism.

CBS 844INS68 and MS D919G polymorphism: early pregnancy loss risk

Cystathionine beta synthase (CBS) and Methionine synthase (MS) maintains the level of homocysteine in blood. Our objective was to study the genetic association of CBS 844ins68 and MS D919G polymorphism with early pregnancy loss (EPL) and Recurrent pregnancy loss (RPL). We investigated 174 EPL patients in which 130 were RPL patients and 180 healthy controls. Genotyping was done through PCR-RFLP for MS D919G polymorphism whereas that for CBS 844ins68 was performed in duplex PCR reaction. Age adjusted odds ratios (AORs) were calculated by logistic regression analysis. The CBS 844ins68 was found to have protective effect rather than having risk for RPL (AORs = 0.49, 95% CI=0.22-1.08, p=0.07). The MS D919G polymorphism also did not differ significantly between patients and controls. This is the first study to see the association of CBS and MS with EPL and more study in ethically different population is needed to confirm its association with EPL.

Association between polymorphisms in folate metabolism genes and maternal risk for Down syndrome: A meta-analysis.

Previous studies have focused on the association between polymorphisms of the genes involved in folate metabolism and Down syndrome (DS); however, the results remain inconclusive. The present meta-analysis was conducted to assess the association between RFC-1 A80G/MTR A2756G/CBS 844ins68 polymorphisms and the maternal risk of DS. Published studies were retrieved from PubMed, Embase, China National Knowledge Infrastructure and Chinese Biomedicine databases. Pooled odds ratios (ORs) with 95% confidence interval (CIs) were calculated using the fixed- or random-effects model. Additionally, test of heterogeneity, cumulative meta-analysis, sensitivity analysis and assessment of bias were also performed. Finally, 11, 11 and 6 studies were deemed eligible for meta-analyses of RFC-1 A80G, MTR A2756G and CBS 844ins68, respectively. A significant association between RFC-1 A80G polymorphism and DS risk was observed for G vs. A (OR=1.19, 95% CI: 1.004–1.40, P=0.04) and the recessive model (OR=1.28, 95% CI: 1.05–1.56, P=0.01). In the stratified analysis by source of control or sample size, a significantly increased risk was observed among hospital-based studies and large-sample groups (>200 subjects), respectively. In addition, the cumulative meta-analysis of the RFC-1 A80G variant revealed a trend toward an association as the amount of data increased. However, for the MTR A2756G and CBS 844ins68 polymorphisms, no obvious association was found for all genetic models. In summary, the present meta-analysis demonstrated that RFC-1 A80G, but not MTR A2756G or CBS 844ins68, was considered as a maternal risk factor for DS in the offspring.

Increased Plasma Homocysteine Level isAssociated with Executive Dysfunction inType 2 Diabetic Patients with Mild Cognitive Impairment.

Homocysteine (Hcy) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. We aimed to investigate the role of Hcy in T2DM patients with mild cognitive impairment (MCI), and to determine whether methylene tetrahydrofolate reductase (MTHFR) C677T or cystathionine beta-synthase (CBS) 844ins68 polymorphism is related to T2DM-associated MCI. We recruited 285 T2DM patients and divided them into two groups, 140 patients with MCI, and 145 healthy-cognition controls, on the basis of Montreal Cognitive Assessment (MoCA) scores. Demographic characteristics, clinical parameters, and neuropsychological tests were assessed. MTHFR C677T and CBS 844ins68 polymorphisms were analyzed. The MCI group exhibited significantly higher plasma total Hcy (tHcy) levels than control group (p < 0.001). Plasma tHcy level was negatively correlated with MoCA scores (p = 0.002), but positively associated with Trail Making Test A and B scores (p = 0.044; p = 0.005, respectively). Multivariable logistic regression model showed that high tHcy level was an independent factor for MCI in T2DM patients. No significant difference was observed in the genotype or allele distributions of MTHFR and CBS between MCI and control groups. We did not find significant MCI risks in MTHFR T allele compared with C allele, and in CBS I allele compared with D allele (OR = 1.361, p = 0.067; OR = 1.048, p = 0.909, respectively). Increased plasma tHcy level was significantly related to T2DM-associated MCI, especially executive dysfunction. Further investigation with a large population size should be conducted to confirm these findings.

Polymorphisms in methylenetetrahydrofolate reductase and cystathionine beta-synthase in oral cancer – a case–control study in southeastern Brazilians

IntroductionOral squamous cell carcinoma (OSCC) is a serious public health problem, due to its high mortality rate and worldwide rising incidence. OSCC susceptibility is mediated by interactions between genetic and environmental factors. Studies suggest that genetic variants encoding enzymes involved in folate metabolism may modulate OSCC risk by altering DNA synthesis/repair and methylation process. ObjectiveThe goals of this study were to evaluate the association of three genotypic polymorphism (MTHFR C677T, MTHFR A1298C and CBS 844ins68) and oral cancer risk in southeastern Brazilians and evaluate the interactions between polymorphisms and clinical histopathological parameters. MethodsThis case–control study included 101 cases and 102 controls in the state of Espírito Santo, Brazil. MTHFR genotyping was done by PCR-RFLP (polymerase chain reaction – restriction fragment length polymorphism) and CBS genotyping by PCR (polymerase chain reaction) analysis. ResultsMTHFR C677T polymorphism was associated with lymph node involvement. Genotype CT+TT acted as a protective factor. MTHFR A1298C AC+CC genotype was associated with tumor differentiation, and possibly with a better prognosis. In risk analysis, no correlation was observed between genotypes and OSCC. ConclusionWe concluded that MTHFR C677T, MTHFR A1298C and CBS 844ins68 polymorphisms were not associated with OSCC risk in southeastern Brazilians; however, we suggest a prognosis effect associated with MTHFR C677T and A1298C polymorphisms in OSCC.

Association of cystathionine β-synthase gene polymorphisms with essential hypertension in ethnic Uyghurs and Hans from Xinjiang

To investigate the cystathione beta synthase (CBS) gene T833C, G919A, 844ins68 polymorphisms and plasma homocysteine (Hcy) levels in ethnic Uyghur and Han patients with essential hypertension (EH) in Xinjiang. Four hundred twenty nine cases including 211 Uyghur and 218 Han EH patients were recruited, whilst 410 healthy individuals including 210 Uyghurs and 200 Hans were used as the controls. Amplification refractory mutation system (ARMS) was adopted to analyze the CBS gene polymorphisms including T833C, G919A and 844ins68. Enzymoimmunoassay was applied to determine the plasma level of Hcy. Chemiluminescence was applied to determine the plasma folic acid and vitamin B12. Compared with the controls, the plasma Hcy level was significantly higher in the EH group in both ethnic Uyghurs and Hans (P < 0.05). Plasma levels of Hcy in T833C, G919A genotypes (for both heterozygotes and homozygotes) were statistically higher than wild types (P < 0.05). A significant difference was detected in G919A polymorphism between the EH patients and controls in both Uyghur and [CM(144.5mm] Han ethnics (Uyghur: x² = 10.264, P < 0.01; Han: x² = 23.075, P < 0.01), and in T833C between the EH patients and controls in ethnic Uyghurs (x² = 40.254, P < 0.01). Logistic regression analysis indicated that age (OR=1.151, P=0.047, 95% CI = 1.002-1.323), T833C (CC) (OR = 1.078, P = 0.003, 95% CI = 1.043-1.114), obesity (OR = 1.284, P = 0.021, 95% CI = 1.038-1.590), hyperhomocysteine (OR = 3.296, P = 0.016, 95% CI = 1.244-8.733) were independent risk factors for EH among ethnic Uygurs, while age (OR = 1.162, P = 0.007, 95% CI = 1.042-1.297), obesity (OR = 3.501, P = 0.003, 95% CI = 1.521-8.060), hyperhomocysteine (OR = 1.046, P = 0.031, 95% CI = 1.011-1.459) were independent risk factors for EH in ethnic Hans after adjusting for confounding factors. Plasma level of Hcy is associated with ethnic Uyghur and Han patients with EH in Xinjiang. CBS gene T833C CC genotype may be associated with the EH among Uyghur ethnics.

CBS c.844ins68 Polymorphism Frequencies in Control Populations: Implications on Nonsyndromic Cleft Lip with or without Cleft Palate

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with substantial clinical and social impact. Folate deficiency is one of the factors that have been associated with increased risk for NSCLP. Polymorphisms in folate and homocysteine pathway genes may act as susceptibility factors. The objective of this study was to evaluate prevalence estimates of cystathionine beta-synthase (CBS) insertion of 68-bp (c.844ins68) polymorphisms and their correlation with NSCLP. A total of 236 unrelated individuals from seven Indian populations and an additional 355 cases with NSCLP and 357 controls without NSCLP were included in this study. We investigated the CBS c.844ins68 polymorphism in all samples. Genotyping was performed with polymerase chain reaction and electrophoresis. The data were statistically analyzed using the chi-square test. The CBS c.844ins68 allele is present in six of the seven populations analyzed, and allele frequencies range from 1.5% in Balija to 9.1% in Sugali populations. The CBS c.844ins68 polymorphism showed a significant protective effect on NSCLP at both genotype (WW versus WI: odds ratio [OR] = 0.54, 95% confidence interval [CI] = 0.31 to 0.95, P = .149) and allele levels (W versus I: OR = 0.56, 95% CI = 0.32 to 0.96, P = .033). The current study observed significant differences in the frequency of the CBS 844ins68 allele across populations. There is a significant association between CBS c.844ins68 polymorphism and cleft lip and palate in the Indian population. Additional studies are warranted to identify the functional variants in the genes controlling homocysteine as etiological contributors to the formation of oral clefts.

The association between the 844ins68 polymorphism in the CBS gene and breast cancer.

IntroductionThe cystathionine beta synthase (CBS) gene plays an important role in homocysteine metabolism because it catalyzes the first step of the transsulfuration pathway, during which homocysteine is converted to cystathionine. Polymorphisms of CBS have been associated with cancer.Material and methodsWe examined the role of the 844ins68 polymorphism by comparing the genotypes of 371 healthy Mexican women with the genotypes of 323 Mexican women with breast cancer (BC).ResultsThe observed genotype frequencies for controls and BC patients were 1% and 2% for Ins/Ins, 13% and 26% for W/Ins, and 86% and 72% for W/W, respectively. We found that the odds ratio (OR) was 2.2, with a 95% confidence interval (95% CI) of 1.5–3.3, p = 0.0001. The association was also evident when comparing the distribution of the W/Ins-Ins/Ins genotypes in patients in the following categories: 1) menopause and high γ-glutamyltransferase (GGT) levels (OR of 2.17, 95% CI: 1.17–4.26, p = 0.02), 2) chemotherapy response and high lactate dehydrogenase (LDH) levels (OR 2.2, 95% CI: 1.08–4.4, p = 0.027), 3) chemotherapy response and high GGT levels (OR 2.46, 95% CI: 1.2–4.8, p = 0.007), and 4) body mass index (BMI) and III–IV tumor stage (OR 3.2, 95% CI: 1.2–8.3, p = 0.013).ConclusionsWe conclude that the genotypes W/Ins-Ins/Ins of the 844ins68 polymorphism in the CBS gene contribute significantly to BC susceptibility in the analyzed sample from the Mexican population.

Cystathionine beta-synthase 844ins68 polymorphism is unrelated to susceptibility to neural tube defects

ObjectiveCystathionine beta-synthase (CBS) 844ins68 polymorphism has been implicated in the development of neural tube defects (NTDs). However, the results of different studies are inconsistent. Thus, we conducted a meta-analysis to further investigate this association. MethodsPublished studies were retrieved from PubMed, Embase, China National Knowledge Infrastructure, and Wanfang Data. Studies that evaluated the association between CBS 844ins68 polymorphism and NTD risk among mothers, children, or fathers were included. The pooled odds ratios with 95% confidence interval were calculated using a fixed effects model or a random effects model. ResultsA total of eight studies on mothers (641 cases and 1145 controls), eight studies on children (852 cases and 1912 controls), and five studies (263 cases and 1562 controls) on fathers were included. The meta-analysis revealed no significant association between CBS 844ins68 polymorphism and NTD risk among mothers, children, and fathers under either genetic model. ConclusionThe present meta-analysis indicates that CBS 844ins68 polymorphism is not a good predictor of risk for NTDs.

Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis

Down syndrome (DS) is the most common chromosomal abnormality. Many studies have assessed the association between maternal gene polymorphisms involved in folate metabolism and the risk of having a DS offspring, but data are conflicting. Our study aimed to arrive at a more accurate estimation. Therefore, we carried out a meta-analysis of 26, 17, 9, 15, 9 and 6 case-control studies on the relationship between maternal methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G, reduced folate carrier 1 A80G and cystathionine β-synthase 844ins68 polymorphisms and the risk of having a DS offspring. The allele contrast and model-free approach were used. Results showed marginal significant associations for MTHFR C677T, overall [odds ratio (OR) = 1.28 (1.22, 1.46) and generalised odds ratio (ORG) = 1.35 (1.16, 1.57)] and in Caucasian [OR = 1.15 (1.03, 1.29) and ORG = 1.20 (1.04, 1.38)], Asian [OR = 1.68 (1.08, 2.63) and ORG = 1.74 (1.08, 2.80)] and Brazilian [OR = 1.22 (1.04, 1.43) and ORG = 1.28 (1.06, 1.55)] populations; for MTRR A66G, overall [OR = 1.22 (1.02, 1.46) and ORG = 1.31 (1.06, 1.62)]; and for RFC1 A80G, overall [OR = 1.16 (1.02, 1.31) and ORG = 1.18 (1.01, 1.37)]. MTHFR A1298C, MTR 12756G and CBS 844ins68 polymorphisms produced non-significant results. Since potential confounders could not be ruled out completely in this meta-analysis, further studies are needed to confirm these results.

Clinical study regarding the link between cystathionine β-synthase 844ins68 polymorphism and maternal risk for Down syndrome

Folic acid is commonly used for the primary prevention of severe congenital malformations and Down syndrome (DS). The objective of this study was to evaluate the frequency of 844ins68 polymorphism of the cystathione beta-synthase (CBS) gene and to verify if the occurrence of this polymorphism is associated with trisomy 21. In the present study we analyzed 72 mothers (ages between 20 and 42 years old) in which those children presented or not DS. Mothers of children with DS (26 cases) were included as study group and those with children without DS and who had never suffered a miscarriage were enrolled as control group (46 cases). Genomic deoxyribonucleic acid (DNA) was isolated from whole peripheral blood collected on ethylenediaminetetraacetic acid, using peqGOLD blood DNA mini kit. The common CBS polymorphism that causes an insertion of 68 bp at the 844 position was further identified. Results. The frequencies of CBS 844ins68 genotypes (ins-/ins-, ins+/ins-) among case mothers were 84.6 and 15.4%, respectively. The corresponding frequencies among controls were 91.3 and 8.7%, respectively. In our study, we did not find any significant differences in genotype frequencies between the two analyzed groups. <br/><a href=

Association between 11 genetic polymorphisms in folate-metabolising genes and head and neck cancer risk

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G, MTHFD1 G1958A, CBS 844ins68, TC2 C776G and A67G, SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ⩾49years (P<0.001), male gender (P=0.03), tobacco habit (P<0.001), MTHFR 1298AC/CC (P=0.028), MTR 2756AG/GG (P=0.010) and RFC1 80AG/GG (P=0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 (P=0.005); age ⩾49years and MTR 2756 AG/GG (P=0.004) and RFC1 80AG/GG (P=0.006) genotypes; male gender and MTHFR 1298 AC/CC (P=0.030), MTR 2756 AG/GG (P=0.006) and RFC1 80 AG/GG (P=0.009); tobacco non-habit and MTHFD1 1958GA/AA (P=0.040); tobacco and MTHFR 1298 AC/CC (P=0.054) and MTR 2756 AG/GG (P=0.010); alcohol non-consume and RFC1 80 AG/GG (P=0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours (P=0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility

Objective Endometriosis has been considered an epigenetic disease. Single nucleotide polymorphisms (SNPs) located in genes encoding enzymes of the folate and choline metabolism may affect DNA methyltransferase activity. Study design We studied 16 SNPs in 12 folate and choline metabolism genes, including BHMT (rs7356530 and rs3733890), BHMT2 (rs625879), CBS (844ins68), CHDH (rs893363 and rs2289205), CHKA (rs7928739), MTHFD1 (rs2236225), MTHFR (rs1801133), MTR (rs1805087), MTRR (rs1801394), PCYT1A (rs712012 and rs7639752), PEMT (rs4244593 and rs4646406) and TCN (rs1801198) in one hundred and sixty-three infertile women with minimal endometriosis and one hundred and fifty fertile women. Results There were no significant differences between genotype and allele frequencies of these gene variants in infertile women with endometriosis ( n = 163) and controls ( n = 150). The lowest, but not statistically significant, p values of the trend test were observed for the CBS 844ins68 and MTR rs1805087 ( p trend = 0.0527 and p trend = 0.0771, respectively) polymorphisms. However, the exhaustive multifactor dimensionality reduction analysis revealed an epistatic interaction between rs1801133 of MTHFR and rs4244593 of PEMT in endometriosis-associated infertility ( p = 0.0240). Conclusions Our results showed moderate evidence for the contribution of SNPs located in genes encoding folate and choline metabolism enzymes to infertility in women with endometriosis.